WO1993022302A1 - N-aryloxy(thio)alkyl-azacycloalcanes utiles en tant qu'antagonistes des canaux calciques - Google Patents

N-aryloxy(thio)alkyl-azacycloalcanes utiles en tant qu'antagonistes des canaux calciques Download PDF

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Publication number
WO1993022302A1
WO1993022302A1 PCT/GB1993/000801 GB9300801W WO9322302A1 WO 1993022302 A1 WO1993022302 A1 WO 1993022302A1 GB 9300801 W GB9300801 W GB 9300801W WO 9322302 A1 WO9322302 A1 WO 9322302A1
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Prior art keywords
formula
piperidinoheptane
compound
benzyloxyphenoxy
phenoxy
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PCT/GB1993/000801
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English (en)
Inventor
Thomas Henry Brown
David Gwyn Cooper
Ronald Joseph King
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Smithkline Beecham Plc
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Priority claimed from GB929208859A external-priority patent/GB9208859D0/en
Priority claimed from GB929208871A external-priority patent/GB9208871D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP93909052A priority Critical patent/EP0637303A1/fr
Priority to KR1019940703826A priority patent/KR950701330A/ko
Priority to JP5519026A priority patent/JPH07506104A/ja
Publication of WO1993022302A1 publication Critical patent/WO1993022302A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms

Definitions

  • the present invention relates to aiyloxyalkylamino and arylthioal ylamino derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of ischaemic stroke.
  • Stroke is reportedly the third most common cause of death in the developed world.
  • Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
  • EP-A-103252 discloses a broad class of aryloxyalkylamino derivatives. These compounds are said to have utility as herbicides.
  • French Patent Application No. 1601591 describes a class of nitrogen-containing heterocyclic compounds derived from phenoxyalkyl alcohols, which are said to be cholesterol-lowering agents.
  • phenoxyalkyl alcohols which are said to be cholesterol-lowering agents.
  • aryloxyalkylamino and aryltWoalkylamino derivatives exhibit activity as calcium channel antagonists.
  • the present invention therefore provides, in a first aspect, use of a compound of formula (I):
  • R 1 represents C ⁇ _6alkyl or Ci.galkoxy; s is zero, 1 or 2; X represents oxygen or sulphur, and
  • n 4, 5 or 6, most preferably 5.
  • q is 6 to 9, most preferably 7.
  • R* preferably represents Cj_6alkyl, such as methyl.
  • X preferably represents oxygen
  • Y is preferably oxygen or a bond.
  • oxygen p is preferably zero and mis preferably zero or 1.
  • m+p is preferably 1 or 2.
  • Ar is phenyl mono-substituted by phenoxy, benzyl, benzyloxy or halo; phenyl disubstituted by halo; or Ar is 2-dibenzofuranyl.
  • Ar is phenyl substituted by benzyl or benzyloxy.
  • tricyclic heteroaryl groups examples include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine.
  • the tricyclic moiety can be linked to the remainder of formula (I) via any suitable ring atom.
  • Suitable substituents for Ph, and tricyclic heteroaryl groups include, for example, 1 to 3 substituents selected ftom halogen, trifluoromethyl, trifluoromethoxy, C ⁇ _4alkyl andC ⁇ _4alkoxy.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Chalky! group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as isopropyl, t-butyl, or sec-pentyl. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts may be used for example in the isolation of the final product and are included within the scope of this invention.
  • the compounds of formula (I) may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.
  • n, q, Rl, s and X are as defined for formula (I) and Ar is an optionally substituted tricyclic heteroaryl group as defined for formula (I); or a salt thereof.
  • the invention also provides a compound of formula (IB)
  • R*, s, n and X are as defined for formula (I) and Ar ⁇ represents phenyl optionally substituted by a group Ph-(CH2) m Y(CH2)p- or a tricyclic heteroaryl group as defined for formula (I), or a salt thereof.
  • n is preferably from 4 to 6, most preferably 5.
  • X preferably represents oxygen.
  • R ⁇ preferably represents C]_4--lkyL
  • Ar ⁇ preferably represents phenyl substituted by a group Ph(CH2) m Y CH2)p".
  • Ar ⁇ represents phenyl substitued by phenoxy, benzyl or benzyloxy. In general the phenyl substituent will preferably be at the 4-position of the phenyl ring relative to the group X.
  • the compounds of the present invention can be prepared by processes analogous to those known in the art
  • the present invention therefore provides in a further aspect, a process for the preparation of a novel compound of formula (I) in particular a compound of formula (IA) or (IB) which comprises:
  • n, R 1 , s and q are as defined in formula (IA) and L 1 is a group displaceable with a nucleophile with a compound of formula (HI) :
  • n, R and s are as defined in formula (IA); or
  • Rl, S, q, X and Ar3 are as hereinbefore defined and A" is a counter anion;
  • the reaction between a compound of formula (II) and a compound of formula (HT) can be carried out under standard conditions.
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • diethyl azodicarboxylate and triphenyl phosphine Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1).
  • This reaction may optionally be effected in the presence of a solvent such as tetrahydrofuran-
  • the leaving group L may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy.
  • reaction may be effected in the absence or presence of solvent such as ⁇ methylformamide or methylethylketone in the presence of a base such as sodium hydride or potassium carbonate and at a temperature in the range 0 to 200°C.
  • solvent such as ⁇ methylformamide or methylethylketone
  • base such as sodium hydride or potassium carbonate
  • the reaction of a compound of formula (TV) with a compound of formula (V) according to process (b) may be effected in conventional manner, for example using excess amine as solvent or alternatively using an organic solvent, such as ethanol or dimethylfo ⁇ namide.
  • the leaving group L 2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction is preferably carried out in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide.
  • Reduction of an amide according to process (c) may be effected using a suitable reducing agent such as lithium aluminium hydride.
  • reductive amination of an aldehyde (NUT) may be effected using a reducing agent such as sodium cyanoborohydride in the presence of a compound of formula (N), according to procedures well known in the art
  • reaction of compounds (IX) and (X) may be effected in an analogous manner to process (a) described above.
  • Reduction of a pyridinium derivative (XI) according to process (f) may be effected for example by hydrogenation, using a noble metal catalyst such as palladium on charcoal, platinum or platinum oxide (Adam's catalyst), suitably in a solvent such as an alcohol e.g. ethanol.
  • a noble metal catalyst such as palladium on charcoal, platinum or platinum oxide (Adam's catalyst)
  • a solvent such as an alcohol e.g. ethanol.
  • Inteiconversion reactions according to process (g) may be carried out using standard methods.
  • a compound of formula (II) can be prepared under standard alkylation conditions by reacting a compound of formula (XD : Formula (XII)
  • the leaving groups L 1 and 1-2 are preferably selected so that the compound of formula (V) reacts selectively with iA
  • I-* is suitably hydroxy and 1-2 is suitably halo.
  • Compounds of formula (TV) can be prepared by reacting a compound of formula (HI) as hereinbefore defined with a compound of formula (XII) as hereinbefore defined.
  • L and 1-2 can be identical, for example halo.
  • the reaction is suitably carried out in the presence of a weak base such as potassium carbonate.
  • the reaction may be carried out under phase transfer conditions using a strong base such as potassium hydroxide.
  • Compounds of formula (V) and (XII) are commercially available or may be prepared by standard methods.
  • Compounds of formula (NT) may be prepared according to general processes (a) and (b) described herein employing an appropriate amide corresponding to formula (II) or (V).
  • Compounds of formula (VII) may be prepared by acylation of a compound of formula (V) for example with an appropriate acid chloride or ester, which may itself be prepared from a compound of formula (HI) by reaction with an appropriate, commercially available bromoalkyl ester or acid, followed if necessary or desired by conversion to an acid chloride.
  • a compound (NIT) may be prepared by a method analogous to process (a).
  • An aldehyde of formula (ND ) may be prepared for example by reduction of the corresponding nitrile using a reducing agent such as diisobutyl aluminium hydride, in the presence of an inert solvent such as toluene. Conveniently reductive amination of the aldehyde is carried out in situ, i.e. the compound of formula (I) is obtained ftom the nitrile in a one-pot reaction without isolation of the intermediate aldehyde.
  • the nitrile may itself be prepard by reacting a compound of formula (TV) wherein L2 is halo with potassium cyanide.
  • Compounds (NDI) may also be prepared by other standard procedures such as reduction of an ester or oxidation of an alcohol.
  • Compounds of formula (IX) may be prepared by methods analogous to any of processes (a) - (d) described herein.
  • a compound (TX) may be obtained by catalytic hydrogenation of a corresponding compound of formula O wherein Ar represents a benzyloxyphenyl group- This therefore provides a further method of converting a compound of formula (I) to a different compound of formula (I).
  • the invention also encompasses any novel intermediates described herein, in particularthose of formulae B), (IV), (VI), (VII), (IX) and (XI).
  • Compounds of the invention have been found to exhibit high calcium influx blocking activity, for example in neurons.
  • the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head or spinal injury, AT S-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
  • Particularly preferred compounds according to the present invention are 7-(4- benzylphenoxy)-l-piperidinoheptane and 7-(4-benzyloxyphenoxy)-l-piperidinoheptane (which may also be named as l-[7-(4-benzylphenoxy)heptyl]piperidine and l-[7-(4- be ⁇ zyloxyphenoxy)heptyl]piperidine) and pharmaceutically acceptable salts thereof.
  • These rompounds The compounds also demonstrate neuroprotective effects in various animal models of ischaemia, when administered post-ischaemia.
  • the invention also provides a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head or spinal injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient
  • the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • Parenteral administration is generally preferred.
  • the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent for example polyethylene glycol, oils, or water with a suspending agent preservative, flavouring or colouring agent
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical ca ⁇ ier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical ca ⁇ ier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical ca ⁇ ier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • Both liquid and solid compositions may contain other excipients known in the pharmaceutical art such as cyclodextrins.
  • composition is in unit dose form such as a tablet capsule or ampoule.
  • dosage unit for oral administration contains preferably from 1 to 250 mg
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg.5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (T) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day.
  • the total daily dosage by oral administration could be in the range 1 to 2000 mg and the total daily dosage by parenteral administration could be in the range 0.1 to 400 mg.
  • the compounds may be administered for a period of continuous therapy, for example for a week or more.
  • a compound of formula fj) or a pharmaceutically acceptable salt therof may be administered in combination or concurrently with one or more other therapeutic agents, for example a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator; an excitatory amino acid antagonist such as an NMD A antagonists; a free radical inhibitor; or a calpain inhibitor.
  • a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator
  • an excitatory amino acid antagonist such as an NMD A antagonists
  • a free radical inhibitor such as a free radical inhibitor
  • a calpain inhibitor a calpain inhibitor
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL 2 , 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCL 2 , 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCL 2 , 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 ⁇ drug was assessed 3 minutes after drug application. Compounds of the invention gave percentage inhibition of plateau Ca 2+ current in the range 35-100%
  • Test compound A 7-(4-Benzyloxyphenoxy)-l-piperidinoheptane hydrochloride
  • Test compound B 7-(4-Benzylphenoxy)-l-piperidinoheptane hydrochloride
  • mice Male Mongolian gerbils weighing between 60-80 g were anaesthetised witii halothane, placed on a heated mat and the carotid arteries occluded. After reperfusion, the animals were sutured and placed in an incubator maintained at body temperature until recovery. The animals were then caged separately and on the 4th day after the day of surgery, they were assessed for locomotor activity using an automated locomotor activity monitoring system. The dosing protocol in these experiments was 30 minutes post-ischaemia then bi.d. for 3 days, injections being given via the i.p. route.
  • test compound A was given 10 mg.kg ⁇ l or 3 mg.kg ** l using the above dosing regime.
  • 10 minutes of occlusion was used and 30 mg.kg'l of test compounds A and B administered 30 minutes post-ischaemia followed by 10 mg.kg"l b.i.d. for 3 days.
  • test compound A at 10 mg.kg ⁇ l produced a significant reversal of the histological impairment in the C Al region of the hippocampus seen in the ischaemic vehicle-treated animals. This dose also produced a slight though statistically non-significant reversal of the ischaemia-induced hyperlocomotion.
  • the higher dose of test compounds A and B used in the second experiment produced a significant reversal of the locomotor deficit induced by the 10 minute period of ischaemia, but did not produce a statistically significant effect on histology.
  • Test compounds were administered i.p. at 30 mg.kg" 1 10 minutes post-operatively, followed by a further dose of 10 mg.kg" one hour post surgery and then twice daily for three days. A 75% reduction in lesion volume was observed for Compound A.
  • Test compound A (10 mg.kg-1 dissolved in 10% HPCD), was infused over 30 minutes. Minor pressor effects, similar to those seen in vehicle treated animals, were observed, together with minor reductions in heart rate. These results indicate that the compound was without significant cardiovascular effects at the dose tested.
  • a tonicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added-
  • 1,7-Dibromoheptane (12.9g) was added dropwise to a stirred solution of 4- benzyloxyphenol (lOg), sodium hydroxide (2.5g), benzyltriethylammonium chloride (0.4g) and water (30ml). The mixture was stirred at 50°C for 18 hours, water (50ml) added and the solution extracted with dichloromethane (2 x 100ml). The combined dichloromethane extracts were dried over magnesium sulphate, solvent was removed and the residue was chromatographed on silica gel eluted with hexane/dichloromethane to give the title compound (4-25g) as a solid, m.p. 56 - 59°C. 4) 6-Piperidinohexanol
  • the title compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (1.5g), 4-fluorophenol (0.84g), triphenylphosphine (1.97g) anddiethyl azodicarboxylate (1.30g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride followed by recrystallision ftom ethyl acetate methanol gave a white solid,(1.27g), m-p. 126-127°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 2,4-dichlorophenol (0.8 lg), triphenylphosphine (1.3 lg) and diethyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride gave a white solid which was recrystallised from acetonitrile, m.p. 176-178°C.
  • the title compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-phenoxyphenol (0.93g), triphenylphosphine (1.31g) and diethyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate, (1.23g), m.p. 176-178°C.
  • the title compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 3-phenoxyphenol (0.93g), triphenylphosphine (1.3 lg) and diethyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate, (0.884g), m.p. 100-101°C.
  • Example 8 The title compound was prepared in a similar manner to Example 8 starting from 7-(4- benzyloxyphenoxy)-l-bromoheptane (1.0g), pyrrolidine (1.13g), potassium carbonate (1.62g) and ethanol (25ml). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride gave a white solid which was recrystallised from acetone, (0.45g), m.p. 132- 134°C.
  • the dichloromethane layer was washed consecutively with water and dilute hydrochloric acid and then dried over magnesium sulphate, the solvent was remove and the residue was chromatographed on silica gel eluted with dichloromethane-methanol and recrystallised from acetonitrile to give the title compound, (0.738g) m.p. 162 - 163°C.
  • the title compound was prepared in a similar manner to Example 1 starting from 6- piperidinohexanol (1.5g), 3,4-dichlorophenol (1.32g), triphenylphosphine (2.12g) and died yl azodicarboxylate (1.40g). Chromatography on silica gel eluted with ⁇ methanol/dichloromethane followed by treatment with ethereal hydrogen chloride and recrystallisation from methanol/ethyl acetate, gave the title compound as white needles, (1.17g), m.p. 138-139°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 9- piperidinonanol (1.2g), 3,4-dichlorophenol (0.84g), triphenylphosphine (1.38g) and diediy azodicarboxylate (0.92g). Chromatography on silica gel eluted with methanol/dichloromethane followed by treatment with ethereal hydrogen chloride and recrystallisation from acetonitrile, gave the tide compound as white needles, (1.25g), m.p. 127-128°C.
  • the title compound was prepared in a similar manner to Example 1 starting from 9- piperidinonanol (1.2g), 4-benzyloxyphenol (1.05g), triphenylphosphine (1.38g) and diediyl azodicarboxylate (0.92g). Chromatography on silica gel eluted widi methanol/dichloromethane followed by treatment with ethereal hydrogen chloride and recrystallisation from acetonitrile, gave die tide compound as white needles, (0.834g), m.p. 144- 145°C. "
  • the tide compound was prepared in a similar manner to Example 1 starting from 8- piperidinooctanol (1.3g), 4-benzyloxyphenol (1.22g), triphenylphosphine (1.60g) and diediyl azodicarboxylate (1.06g). Chromatography on silica gel eluted with methanol/dichloromethane followed by treatment with ethereal hydrogen chloride and recrystallisation from ethyl acetate, gave the tide compound as white needles, (0.793g), m.p. 141 - 143°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 8- piperidinooctanol (1.3g), 4-phenoxyphenol (1.12g), triphenylphosphine (1.60g) and diediyl azodicarboxylate (1.06g). Chromatography on silica gel eluted with methanol/dichloromethane followed treatment with ethereal hydrogen chloride and recrystallisation from ethyl acetate, gave the tide compound as a white solid, (0.98g), m- 75 - 76°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 6- piperidinohexanol (1.5g), 4-benzyloxyphenol (1.62g), triphenylphosphine (1.12g) and diediyl azodicarboxylate (1.40g). Chromatography on silica gel eluted with methanol/dichloromethane followed by treatment with ethereal hydrogen chloride and recrystallisation from ethyl acetate, gave the tide compound as a white solid, (1.33g), m. 174 - 175°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-[2-(4-chlorophenyl)ed ⁇ yl]phenol (1.19g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromediane followed by treatment witii ethereal hydrogen chloride and recrystallisation ftom acetonitrile, gave the tide compound as white needles, (0.853g), m.p. 167 - 169°C. Found: C, 69.87; H, 8.09; N, 3.10; Cl, 15.43% (C26H36CINO2-HCI) requires: C, 69.32; H, 8.28; N, 3.11; Cl, 15.74%
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (3.0g), trans-4-hydroxystilbene (3.01g), triphenylphosphine (3.93g) and diediyl azodicarboxylate (2.61g). Chromatography on silica gel eluted with methanol/dichloromethane gave a white solid (4.056g). A sample of this material (1.75g) was treated with ethereal hydrogen chloride to give a white solid which was recrystallised from ethanol, to give the tide compound, (1.145g), m.p.219-220°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-benzyloxyphenol (1.14g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted witii methanol/chloroform and treatment with ethereal hydrogen chloride followed by recrystallision from acetonitrile gave the tide compound as white needles,(1.94g), m.p. 173-174°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-benzylphenol (0.93g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride followed by recrystallision from ethyl acetate/methanol gave the tide compound as a white solid,(1.94g), m.p.95-96°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (2.0g), 2-benzylphenol (1.84g), triphenylphosphine (2.62g) and diediyl azodicarboxylate (1.74g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride followed by recrystallision from ethyl acetate/methanol gave the tide compound as a white solid,(1.17g), m.p. 118-120°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-methoxyphenol (0.62g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromethane and treatment with ethereal hydrogen chloride followed by recrystallision from ethyl acetate/methanol gave the tide compound as white needles,(1.143g), m.p. 128-130°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), 4-rerr-butylphenol (0.75g), triphenylphosphine (1.3 lg) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted with methanol/dichloromediane and treatment with ethereal hydrogen chloride followed by recrystallision from methanol/ethyl acetate gave the tide compound as a white solid, (0.779g), m.p. 170-171°C.
  • the tide compound was prepared in a similar manner to Example 1 starting from 7- piperidinoheptanol (l.Og), sesamol (0.69g), triphenylphosphine (1.3 lg) and diediyl azodicarboxylate (0.87g). Chromatography on silica gel eluted witii methanol/chlorofo ⁇ n and treatment with ethereal hydrogen chloride followed by recrystallision from methanol/ethyl acetate gave the tide compound as a white solid, (1.16g), m.p. 141-142°C. Found: C, 63.94; H, 8.18; N, 3.99; Cl, 10.38% (C 19 H 2 9NO3-HCl) requires: C, 64.11; H, 8.49; N, 3.93; Cl, 9.96%
  • the tide compound was prepared in a similar manner to Example 1 starting from 7-(4- hydroxyphenoxy)-l-piperidinoheptane (1.45g), 3,4-dichlorobenzyl alcohol (1.885g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). The solvent was removed and d e residue was dissolved in dichloromethane. This solution was washed thoroughly with dilute hydrochloric acid, dried over sodium sulphate and evaporated. Chromatography on silica gel eluted witii methanol/dichloromethane and recrystallisation from ethanol, gave the tide compound as a white solid, (0.827g), m.p. 184-186°C.
  • the tide compound was prepared in a similar manner to Example 26 starting from 7-(4- hydroxyphenoxy)-l-piperidinoheptane (1.45g), 4-methoxybenzyl alcohol (0.69g), triphenylphosphine (1.31g) and diediyl azodicarboxylate (0.87g). Recrystallisation from acetonitrile gave the title compound as a white crystalline solid, (0.519g), m.p. 172- 176°C.
  • the tide compound was prepared in a similar manner to Example 26 starting from 7-(4- hydroxyphenoxy)-l-piperidinoheptane (1.45g), 4-fluorobenzyl alcohol (0.63g), triphenylphosphine (1.3 lg) and diediyl azodicarboxylate (0.87 g). Recrystallisation from acetonitrile gave the tide compound as a white crystalline solid, (0.782g), m.p. 167- 168°C.
  • Example 8 The product of Example 8 (l.Og) was equilibrated between etiiyl acetate and 0.5N NaOH. The aqueous fraction was re-extracted with ethyl acetate and die combined organic extracts washed (H2O, brine), dried (anhydrous Na2SO4) and evaporated to dryness to give a colourless oil. This oil was dissolved in methanol/ethyl acetate and methane sulphonic acid (0.23g, 1 equivalent) in methanol added. The mixture was concentrated and stood overnight in the fridge to produce die tide compound (0.86g) as white crystals, m.p. 146-148°C.
  • Example 8 The product of Example 8 (l.Og) was equilibrated between dichloromethane and N NaO The aqueous fraction was re-extracted with dichloromethane (2X) and d e combined organic extracts washed (H2O, brine), dried (MgSO.4) and evaporated to dryness to give colourless oil. This oil was dissolved in boiling methanol and (+)-tartaric acid (0.36g, I equivalent) in methanol added. The mixture was concentrated, hot ethyl acetate added an further concentrated to give a white crystalline solid (1.15g). This material was crystallised first from methanol/ethyl acetate and finally from methanol/water to give the tide compound (0.52g) as a white crystallline solid, m.p. 83-84°C.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co-solven such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
  • Suspending agent e.g. Xantiian gum, microcyrstralline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin

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Abstract

L'invention concerne l'utilisation de composés de la formule (I) dans laquelle n est compris entre 3 et 8; q est compris entre 5 et 11; R1 représente un alkyleC¿1?-C6 ou un alcoxyC1-C6; s est égal à zéro, 1 ou 2; X représente un oxygène ou un soufre; et Ar représente un phényle, le cas échéant substitué par 1-3 substituants choisis parmi halo, alkyleC1-C8, alcoxyC1-C8, alkylènedioxyC1-C2, trifluorométhyle, trifluorométhyloxy, ou un groupe Ph-(CH2)m-Y-(CH2)p-, où Ph représente un phényle le cas échéant substitué, m et p sont indépendamment compris entre 0 et 4 et Y représente une liaison, O, S ou CH=CH, une condition à satisfaire étant que m + p ne soit pas supérieur à 4, Ar peut également représenter le groupe hétéroaryle tricyclique (a) suivant, le cas échéant substitué dans lequel Y?1¿ représente Y(CH¿2?)x, où x est égal à 0 ou 1 et Y représente O, S ou NR, où R représente un hydrogène ou un alkyleC1-C4, Z représente (CH2)r ou -CH=CH-, r est égal à 0, 1 ou 2. Ar peut encore représenter un système de cycles tricyclique déshydro correspondant. L'invention concerne également les sels de ces composés acceptables sur le plan pharmaceutique. Ces composés et les sels en question sont utilisés dans la production de médicaments pour le traitement d'états où il y a lieu d'administrer un antagoniste des canaux calciques. En outre, l'invention concerne de nouveaux composés de la formule (I), leurs procédés de préparation et des compositions pharmaceutiques les contenant.
PCT/GB1993/000801 1992-04-24 1993-04-15 N-aryloxy(thio)alkyl-azacycloalcanes utiles en tant qu'antagonistes des canaux calciques WO1993022302A1 (fr)

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EP93909052A EP0637303A1 (fr) 1992-04-24 1993-04-15 N-aryloxy(thio)alkyl-azacycloalcanes utiles en tant qu'antagonistes des canaux calciques
KR1019940703826A KR950701330A (ko) 1992-04-24 1993-04-15 칼슘 통로 길항제로서 유용한 n-아일옥시(티오)알킬-아자사이클로알칸(n-aryloxy(thio)alkyl-azacycloadanes useful as calcium channel antagonists)
JP5519026A JPH07506104A (ja) 1992-04-24 1993-04-15 カルシウムチャネル拮抗物質として有用なｎ−アリールオキシ（チオ）アルキルーアザシクロアルカン

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WO1995011238A1 (fr) * 1993-10-22 1995-04-27 Smithkline Beecham Plc Amines heterocycliques pour le traitement des acces ischemiques
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US20210309623A1 (en) * 2020-03-11 2021-10-07 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

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EP0082005A2 (fr) * 1981-12-14 1983-06-22 Syntex (U.S.A.) Inc. Naphtoxyalkylamines et composés analogues, leur préparation et compositions anti-inflammatoires les contenant
EP0274867A2 (fr) * 1986-12-10 1988-07-20 Schering Corporation Composés pharmaceutiques actifs
WO1988006580A1 (fr) * 1987-02-25 1988-09-07 Schering Aktiengesellschaft Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie
EP0410359A1 (fr) * 1989-07-27 1991-01-30 F. Hoffmann-La Roche Ag Dérivés substitués de l'aminoalkoxybenzène
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GB2078217A (en) * 1980-06-14 1982-01-06 Beecham Group Ltd Phenolic ethers, their preparation and use
EP0082005A2 (fr) * 1981-12-14 1983-06-22 Syntex (U.S.A.) Inc. Naphtoxyalkylamines et composés analogues, leur préparation et compositions anti-inflammatoires les contenant
EP0274867A2 (fr) * 1986-12-10 1988-07-20 Schering Corporation Composés pharmaceutiques actifs
WO1988006580A1 (fr) * 1987-02-25 1988-09-07 Schering Aktiengesellschaft Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie
EP0410359A1 (fr) * 1989-07-27 1991-01-30 F. Hoffmann-La Roche Ag Dérivés substitués de l'aminoalkoxybenzène
EP0470514A1 (fr) * 1990-08-07 1992-02-12 Otsuka Pharmaceutical Co., Ltd. Dérivés de carbostyriles et compositions pharmaceutiques les contenant

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011238A1 (fr) * 1993-10-22 1995-04-27 Smithkline Beecham Plc Amines heterocycliques pour le traitement des acces ischemiques
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
EP0755923A4 (fr) * 1995-01-23 1997-04-09 Suntory Ltd Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
US6048876A (en) * 1995-01-23 2000-04-11 Suntory Limited Medicament for the alleviation or treatment of symptom derived from ischemic disease and compound useful therefor
US6469010B1 (en) 1995-01-23 2002-10-22 Suntory Limited Medicament for the alleviation or treatment of symptom derived from the ischemic disease and compound useful thereof
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US20210309623A1 (en) * 2020-03-11 2021-10-07 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

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AU3959893A (en) 1993-11-29
SI9300217A (sl) 1993-12-31
CN1083055A (zh) 1994-03-02
JPH07506104A (ja) 1995-07-06
CA2133984A1 (fr) 1993-11-11
EP0637303A1 (fr) 1995-02-08
IL105495A0 (en) 1993-08-18
MA22880A1 (fr) 1993-12-31
KR950701330A (ko) 1995-03-23

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